Conformational properties of trans-2-halo-acetoxycyclohexanes: 1H NMR, solvation and theoretical investigation

Article abstract of DOI:10.1016/j.molstruc.2004.08.017

Conformational analyses of trans-2-halo-acetoxycyclohexanes have been performed through NMR, theoretical calculations and solvation theory. The solvent dependence of coupling constants analysed together with solvation parameters of the main calculated geo

Full text of DOI:10.1016/j.molstruc.2004.08.017

Journal of Molecular Structure 734 (2005) 211–217
www.elsevier.com/locate/molstruc
Conformational properties of trans-2-halo-acetoxycyclohexanes:
1H NMR, solvation and theoretical investigation
a
Matheus P. Freitas , Claudio F. Tormena , Roberto Rittner , Raymond J. Abraham
b
a,
c,
*
*
´
aPhysical Organic Chemistry Laboratory, Chemistry Institute, State University of Campinas, Caixa Postal 6154, 13084-971 Campinas, SP, Brazil
b
ˆ
Chemistry Department, Faculdade de Filosofia Ciencias e Letras da Universidade de Sa˜o Paulo, FFCLRP-USP., Av. Bandeirantes,
3900, 14040-901 Ribeira˜o Preto, SP, Brazil
cChemistry Department, University of Liverpool, P.O. Box 147, Liverpool L69 3 BX, UK
Received 29 June 2004; revised 24 August 2004; accepted 26 August 2004
Abstract
Conformational analyses of trans-2-halo-acetoxycyclohexanes have been performed through NMR, theoretical calculations and solvation
theory. The solvent dependence of coupling constants analysed together with solvation parameters of the main calculated geometries allowed
the determination of both the individual couplings and difference energies between the possible ax–ax and eq–eq conformations. For all the
halo-compounds eq–eq is the most stable form in the vapour phase and in solution. The molar fractions (naa) of the ax–ax conformer are 0.28,
0.30, 0.28 and 0.22 in the vapour phase for fluoro (1), chloro (2), bromo (3) and iodo (4) derivatives, respectively, decreasing to 0.06, 0.10,
0.12 and 0.12 in DMSO, calculated through MODELS and BESTFIT, using the solvation theory. The governing factors of these conformational
equilibria are the classical steric and electrostatic interactions, as well as the ‘gauche effect’, especially for the fluoro compound. The acetoxy
group effect has also been compared with previous results for the hydroxy and methoxy derivatives.
q 2004 Elsevier B.V. All rights reserved.
Keywords: Conformational analysis; 1H NMR spectroscopy; Solvation theory; Theoretical calculations
1. Introduction
their respective methyl ethers the population of the eq–eq
form is not so large as it is for the alcohols, the equilibration
being governed by steric and dipolar factors, as well as the
‘gauche effect’ [3,6,7]. In the present work, we report a
conformational study of compounds that are analogous to
the trans-2-halocyclohexanols and their methyl ethers—the
trans-2-halo-acetoxycyclohexanes, in order to investigate
their conformational preferences and evaluate the acetoxy
group effect in relation to the hydroxy and methoxy groups.
Cyclohexyl acetates have special interest in the pharma-
ceutical chemistry field, since, for instance, they can act as
substrates of acetylcholinesterase and muscarinic agents, as
reported by Kay et al. [8], their conformation and
stereochemistry being decisive on their activities. Recent
studies, utilising trans-2-fluorocyclohexanol and its corre-
sponding acetate, have also been carried out in order to
investigate their syntheses and deracemisation [9,10].
According to the physical–organic chemistry point of
The conformation of the six-membered ring in cyclohex-
ane derivatives, in which two substituents may occupy
either the axial or equatorial positions, represents one of the
important topics in stereochemistry, especially in the case of
trans-1,2-disubstituted cyclohexanes, which are useful
models to rationalise the governing factors in conformation-
al equilibria [1–3]. Previous works have been carried out in
order to determine the conformational preferences of trans-
2-halocyclohexanols and their methyl ethers [2–6]. It has
been verified that, in the case of the halohydrins, intra and/or
intermolecular hydrogen bonding leads the conformational
equilibria towards the eq–eq conformer [2–5], while for
* Corresponding authors. Tel.: C55 19 3788 3150; fax: C55 19 3788
3023.
E-mail address: rittner@iqm.unicamp.br (R. Rittner).
0022-2860/$ - see front matter q 2004 Elsevier B.V. All rights reserved.
doi:10.1016/j.molstruc.2004.08.017

212
M.P. Freitas et al. / Journal of Molecular Structure 734 (2005) 211–217
view, another relevant aspect is the fact that, besides ring
interconversion, the rotation around the acetoxy group, in
trans-2-substituted acetoxycyclohexanes, may generate
several rotamers for both the ax–ax and eq–eq confor-
mations. It is known that the s-cis preference is large in the
moiety C–O–CZO (dihedral angleZ08) of methyl acetate
[11], while the occurrence of the s-trans form, due to
rotational equilibrium, can be considered negligible.
Literature data was confirmed by calculating the potential
energy surface (PES) for methyl acetate, at the B3LYP/6-
31G(d,p) level, which showed that the energy difference
between the two forms is around 7.8 kcal/mol in favour of
the s-cis conformer, suggesting that it is the exclusive
geometry in the vapour and condensed phases. Despite the
relative instability of the s-trans geometry, the energies of
all possible conformations were determined by rotation
around the H–C–O–C(ZO) dihedral angle for the trans-2-
substituted-acetoxycyclohexanes (Fig. 1).
2. Experimental
2.1. Compounds
trans-2-Fluoro-acetoxycyclohexane (1) was synthesised
through an overnight reaction between trans-2-fluorocy-
clohexanol and acetyl chloride, in diethyl ether, at room
temperature (bpZ72–78 8C/10 mmHg). trans-2-Fluorocy-
clohexanol was obtained according to a literature pro-
cedure [2]. The chloro derivative (2) was prepared by
reacting cyclohexene, acetic acid and N-chlorosuccinimide
at 70–80 8C for 1 h, it being necessary to cool the flask in
an ice bath immediately after stirring (bpZ73–75 8C/
1 mmHg). The bromo derivative (3) was synthesised in a
similar way, using N-bromosuccinimide, at room tempera-
ture for 30 min (bpZ85 8C/1 mmHg). The iodo derivative
(4) was obtained by stirring cyclohexene, acetic acid and
N-iodosuccinimide, in chloroform, for 30 min at room
temperature, the mixture then being treated according to a
literature procedure [18].
Recent advances in computational chemistry, which
allow the determination of molecular parameters with a high
degree of confidence, leading to accurate geometries for the
application of solvation theory, were an important factor in
this study, and showed that it was not necessary to use
4-tert-butyl derivatives as reference models, since the
combination of these theoretical and solvation methods,
together with 1H NMR spectroscopy, gave a complete
account of the title compound equilibrations in a variety of
solvents.
2.2. Theoretical calculations
The geometries and free energies for the stable
conformations of 1–4 were obtained after optimisations at
the B3LYP/6-311CCg(d,p) (1–3) and B3LYP/3-21 g (4)
levels available in the GAUSSIAN98 program [19]. The
possible conformers are shown in Fig. 2 and their
corresponding relative energies and dipole moments are
presented in Table 1. The main conformations of 1–4 (one
ax–ax and another eq–eq) were introduced in the MODELS
program [12], which gave the reaction field parameters
(Table 2). These parameters, together with the data of
adequate coupling constants, in different solvents, allowed
the determination of the conformational isomerism in trans-
2-halo-acetoxycyclohexanes. The reaction field parameters
k, h, l and VM are terms related to the solute dipole moment,
quadrupole moment, refractive index and the molar volume,
respectively.
The solvation theory applied here has been already fully
described [12], and the methodology used, which is based
on the dependence of adequate coupling constants of the
solvent dielectric constant, and further analysis through
MODELS and BESTFIT programs [12], can also be found in
several recent papers [13–17].
2.3. NMR experiments
The NMR spectra were obtained on Varian GEMINI 300
and INOVA 500 spectrometers, operating at 300.07 and
499.88 MHz for 1H, and at 75.45 and 125.70 MHz for 13C,
respectively. Spectra were of ca. 20 mg cmK3 solutions
with a probe temperature of 298 K. The low temperature
spectra were acquired at 183 K in 1:1 CS2/acetone-d6
solutions. Spectra were all referenced to Me4Si and the
1
typical conditions for the H spectra were: spectral width
2500 and 4000 Hz with 32 K data points and zero filled to
128 K to give a digital resolution of 0.03 Hz, and gauss
window of 0.450 s centred at 0.450 s.
Fig. 1. Conformational equilibrium for trans-2-substituted-acetoxycyclo-
hexanes. The arrow indicates the bond which rotates for generation of
rotamers in each of the s-cis and s-trans forms of the ax–ax and eq–eq
conformers.
For the gCOSY and HSQC experiments, Varian standard
pulse sequences were used. gCOSY typical conditions were
16 transients, accumulated into 2 K data points with 128

M.P. Freitas et al. / Journal of Molecular Structure 734 (2005) 211–217
213
Fig. 2. Possible conformations of trans-2-halo-acetoxycyclohexanes. The acetyl group may present the C–O–CaO moiety with both the s-cis and s-trans
geometries (see Fig. 1), with the s-cis far more stable than s-trans in the vapour phase. The eq–eq gC conformation with the dihedral angle C–O–CaO s-cis is
not a minimum for all compounds, while ax–ax anti for 2 and 4, eq–eq gK for 1 and 2, and eq–eq gC for 3 and 4 are not minima when the dihedral angle C–O–
CaO is s-trans.
experiments, with a pulse width 12.9 ms, sweep width of ca.
5800 Hz and AT of 0.17 s. The FID was zero filled to 2 K
data points (F2) and 2 K data points (F1).
2.3.1. trans-2-Fluoro-acetoxycyclohexane (1)
RMN-1H (CCl4, 499.88 MHz; d in ppm, J in Hz): d 1.25
(2H, m, H5 and H6), 1.34 (1H, m, H4), 1.52 (1H, m, H3), 1.61
0
(1H, m, H4 ), 1.69 (1H, m, H5 ), 1.97 (3H, s, CH3), 2.02 (2H,
0
The chemical shifts for the compounds studied are
presented below and the key to atom numbering is shown in
Scheme 1.
0
0
m, H4 and H6 ), 4.29 (1H, ddt, 4.73, 8.16 and 9.92, H1) and
4.74 (1H, dddd, 4.73, 8.16, 9.99 and 50.04, H2). RMN-13C
(CCl4, 125.70 MHz; d in ppm): d 20.6 (CH3), 22.6 (d, 9.7,
C5), 22.8 (d, 1.9, C4), 29.0 (d, 5.8, C6), 30.1 (d, 19.2, C3),
72.1 (d, 19.2, C1), 90.6 (d, 179.9, C2) and 168.2 (CaO).
Table 1
B3LYP/6-311CCg(d,p) results for the s-cis conformersa of trans-2-halo-
acetoxycyclohexanes
mc
qH–C–O–
d
C(aO)
b
2.3.2. trans-2-Chloro-acetoxycyclohexane (2)
RMN-1H (CCl4, 499.88 MHz; d in ppm, J in Hz): d 1.26
Compound
Grel
0
(2H, m, H5 and H6), 1.37 (1H, m, H4), 1.65 (1H, m, H5 ),
0
1.69 (1H, m, H3), 1.72 (1H, m, H4 ), 1.98 (3H, s, CH3), 2.06
1
aa
gC
1.39
1.49
8.09
0
3.42
3.15
1.80
3.09
2.34
3.64
3.26
1.86
3.17
2.56
3.68
3.30
1.90
3.27
2.62
3.34
2.93
2.12
2.41
2.37
22
328
175
335
176
31
gK
anti
gK
0
0
(1H, m, H3 ), 2.17 (1H, m, H6 ), 3.73 (1H, dt, 4.50 and 8.75,
H1) and 4.69 (1H, ddd, 4.41, 8.75 and 9.94, H2). RMN-13C
(CCl4, 125.70 MHz; d in ppm): d 20.4 (CH3), 22.9 (C5), 24.1
(C4), 30.2 (C6), 34.2 (C3), 59.5 (C2), 74.7 (C1) and 167.6
(CaO).
ee
anti
gC
gK
3.55
1.51
2.59
8.80
0
2
3
4
aa
328
181
337
176
31
anti
gK
ee
anti
gC
gK
3.34
1.61
2.53
8.66
0
Table 2
Reaction field parametersa for 1–4
aa
330
181
342
176
40
Compound
k (kcal -
molK1
h (kcal -
molK1
l
VM (cm3
molK1
anti
gK
)
)
)
ee
anti
gC
gK
3.31
0.59
0.96
7.36
0
1
2
3
4
aa
ee
aa
ee
aa
ee
aa
ee
2.8604
2.3350
3.0690
2.3276
3.0492
2.4076
2.5514
1.2601
1.3339
6.3210
1.4048
5.6948
1.3512
5.3130
0.8939
5.2670
0.5173 148.648
0.5173 148.648
0.5548 156.988
0.5548 156.988
0.5753 161.468
0.5753 161.468
0.6514 167.596
0.6514 167.596
aa
320
181
322
177
anti
gK
ee
anti
0.92
a
s-cis designation refers to the C–O–CaO dihedral angle.
Grel in kcal molK1
m in debye.
b
c
d
.
a
k and h are the dipolar and quadrupolar terms, respectively, l is the term
related to the solute refractive index and VM is the molar volume.
q in degrees.

214
M.P. Freitas et al. / Journal of Molecular Structure 734 (2005) 211–217
A basic assumption for the use of coupling constants in
conformational analysis is that their changes, with the
solvent, are solely due to changes in the conformer
3
populations. If this is the case, then the plots of JH H vs.
1
2
3JH H for any given compound should be linear. This was
2
3
found to be the case for the four compounds described here,
with correlation coefficients of 0.96, 0.92, 0.96 and 0.98 for
fluoro, chloro, bromo and iodo compounds, respectively.
These values can be enhanced by excluding CDCl3 from the
plot, since the couplings corresponding to this solvent do not
fit well with the expected trend in some cases. This is due to
an intermolecular hydrogen bonding between the solvent
(CDCl3) and the solute (CaO group) in the eq–eq form,
which favours this conformation [20]. However, this effect
is much less important in the case of trans-2-halo-
acetoxycyclohexanes (1–4), than for their respective methyl
ethers and alcohols [3,20]. Even so, the 3JH H coupling, in
Scheme 1.
2.3.3. trans-2-Bromo-acetoxycyclohexane (3)
RMN-1H (CCl4, 499.88 MHz; d in ppm, J in Hz): d 1.29
(1H, m, H5), 1.32 (1H, m, H6), 1.40 (1H, m, H4), 1.69 (2H, m,
0
H4 and H5 ), 1.82 (1H, m, H3), 1.99 (3H, s, CH3), 2.10(1H, m,
0
0
0
H6 ), 2.28 (1H, m, H3 ), 3.85 (1H, dt, 4.49 and 8.87, H1) and
4.76 (1H, ddd, 4.31, 8.87 and 10.42, H2). RMN-13C (CCl4,
125.70 MHz; d in ppm): d 20.5 (CH3), 23.0 (C5), 25.1 (C4),
30.7 (C6), 35.1 (C3), 51.6 (C2), 74.8 (C1) and 167.6 (CaO).
1
2
CDCl3, is not recommended to be considered in this MODELS/
BESTFIT [12] analysis.
2.3.4. trans-2-Iodo-acetoxycyclohexane (4)
RMN-1H (CCl4, 499.88 MHz; d in ppm, J in Hz): d 1.26
1
Low temperature H NMR experiments (183 K) were
0
(2H, m, H4 and H6), 1.32 (1H, m, H5), 1.53 (1H, m, H4 ),
0
1.73 (1H, m, H5 ), 1.78 (1H, m, H3), 2.00 (3H, s, CH3), 2.09
performed for compounds 1–4 in CS2/acetone-d6 (1:1) in
order to observe the two separate conformers and measure
the individual coupling constants. The ax–ax conformer
could not be identified at 183 K, due to its negligible amount
at this temperature, but the 3JH H intrinsic couplings could
0
0
(1H, m, H6 ), 2.38 (1H, m, H3 ), 3.85 (1H, dt, 4.30 and 9.34,
H1) and 4.77 (1H, ddd, 4.21, 9.34 and 10.80, H2). RMN-13C
(CCl4, 125.70 MHz; d in ppm): d 20.6 (CH3), 23.3 (C5), 26.7
(C4), 30.6 (C2), 31.1 (C6), 37.2 (C3), 75.7 (C1) and 167.5
(CaO).
1
2
be measured for the eq–eq conformer, despite signal
broadening, as a consequence of the low temperature
(183 K) at which the NMR spectra were acquired. They
were 8.8, 9.8, 10.1 and 10.5 Hz for fluoro, chloro, bromo
3
and iodo compounds, respectively. The trends in JH H
3. Results
1
2
couplings obtained at low temperature are reproduced by the
couplings calculated for the main geometries of 1–4,
through the molecular mechanics PCMODEL program [21],
despite the uncertainties of the PCMODEL calculations caused
by the unrefined PCMODEL geometries used in the calculation
or to approximations in its basic equation, which depends on
the exact value of the H–C–C–H dihedral angle. The
3.1. NMR coupling constants
The hydrogen chosen for the extraction of the coupling
constants to be studied in this work is H-2, since it shows a
clear ddd pattern (dddd for fluorine derivative, due to the
2JH F coupling), very suitable for our purposes. Table 3
2
PCMODEL intrinsic couplings were: 3JH
Z7.87, 8.94, 9.26
1aH2a
3
3
3
2
shows the data for JH H ; JH H ; JH H and JH F: It can
0
be seen that, with exception of JH H ; which is averaged
2
1
2
3
2
3
2
3
and 9.85 Hz for fluoro, chloro, bromo and iodo compounds,
respectively, and 3JH Z3.83, 3.18, 3.04 and 2.62 Hz,
2
3
between J2e,3a and J2a,3e (similar in magnitude), in all other
cases the couplings follow a regular tendency with the
increase in the dielectric constant (3) of the solvent. 3JH H
1eH2e
respectively. Therefore, the observed trends in the intrinsic
values for the low temperature values and for the calculated
values through PCMODEL are the same, although they
differ by ca. 1 Hz, due to the uncertainties of the latter
1
2
has been shown in this work, since it is very convenient as
an adequate coupling for the present study.
Table 3
Coupling constants 3JH H
; ;
3JH H 3JH H for 1–4, and 2JH F for 1, respectively
1 2 2 3 2
0
2
3
Solvent
3
1
2
3
4
CCl4
2.24
4.81
4.73, 8.16, 9.99, 50.04
4.85, 8.41, 10.43, 50.45
4.90, 8.43, 10.32, 50.61
4.78, 8.45, 10.34, 50.66
4.91, 8.52, 10.48, 50.77
4.96, 8.60, 10.55, 50.82
4.79, 8.32, 10.15, 50.43
4.41, 8.77, 9.94
4.42, 9.00, 10.49
4.34, 9.00, 10.63
4.34, 9.06, 10.58
4.59, 9.26, 10.74
4.40, 9.31, 10.91
4.47, 8.89, 10.10
4.31, 8.87, 10.42
4.39, 9.19, 10.90
4.37, 9.16, 10.86
4.42, 9.35, 10.87
4.44, 9.42, 11.04
4.45, 9.46, 11.19
4.38, 8.96, 10.52
4.21, 9.34, 10.80
4.33, 9.48, 11.12
4.31, 9.53, 11.07
4.26, 9.57, 11.23
4.29, 9.68, 11.32
4.30, 9.75, 11.41
4.20, 9.37, 10.88
CDCl3
Pyridine-d5
Acetone-d6
CD3CN
12.40
20.70
37.50
46.70
DMSO-d6
Pure liquid
a
–
a
Interpolated value of 3 for 1 is 8.2, for 2, 7.6, for 3, 4.6 and for 4, 3.6.

M.P. Freitas et al. / Journal of Molecular Structure 734 (2005) 211–217
215
Table 4
Conformer energy differences (kcal molK1), experimental and calculated (in parenthesis) coupling constants (Hz) for 1–4, in selected solvents, and mole
fraction of the axial–axial conformer
Solventa
Eaa–Eee
naa
3
J
H1H2
1
2
3
4
1
2
3
4
1
2
3
4
Vapour
0.55
1.17
1.77
1.87
2.00
2.06
1.67
0.50
0.95
1.36
1.43
1.52
1.56
1.28
0.55
0.96
1.36
1.43
1.52
1.55
1.18
0.75
1.03
1.25
1.28
1.33
1.35
1.13
0.28
0.12
0.05
0.04
0.03
0.03
0.06
0.30
0.17
0.09
0.08
0.07
0.06
0.10
0.28
0.16
0.09
0.08
0.07
0.07
0.12
0.22
0.15
0.11
0.10
0.09
0.09
0.12
CCl4
8.16 (8.09)
8.43 (8.45)
8.45 (8.48)
8.52 (8.52)
8.60 (8.53)
8.32 (8.41)
8.77 (8.60)
9.00 (9.09)
9.06 (9.15)
9.26 (9.21)
9.31 (9.24)
8.89 (9.01)
8.87 (8.74)
9.16 (9.26)
9.35 (9.33)
9.42 (9.40)
9.46 (9.43)
8.96 (9.06)
9.34 (9.26)
9.53 (9.58)
9.57 (9.62)
9.68 (9.68)
9.75 (9.70)
9.37 (9.41)
Pyridine-d5
Acetone-d6
CD3CN
DMSO-d6
Pure liquid
a
Data for chloroform solutions were not included, since compounds 1–4 form hydrogen bonds with chloroform leading to significant deviations in the plot of
3
3JH H vs. JH H
:
1
2
2
3
method. The low temperature coupling constants will be
compared with the BESTFIT [12] calculated values to evaluate
the joint NMR, theoretical and solvation calculations
method.
Jobs Z naaJaa CneeJee naa Cnee Z 1 naa=nee
Z expðKDE=RTÞ DE Z Eaa KEee
(1)
The solvent data were then used with the solvation theory to
search for the best solution for both the conformer energies
and the values of 3J1e,2e and 3J1a,2a. This was achieved using
the program BESTFIT [12]. This calculates the couplings in all
solvents from Eq. (1) for any given value of DEV, using the
solvation energy calculated by MODELS [12], and then
compares the observed and calculated couplings. The best
agreement between both data are given in Table 4. The
molar fraction of the ax–ax conformer of the trans-2-halo-
acetoxycyclohexanes, calculated through Eq. (1), are also
given in Table 4, together with the calculated 3J1,2 couplings
and the conformers’ energy differences, in each solvent. The
rms errors of the observed vs. calculated couplings were
0.06, 0.12, 0.09 and 0.06 Hz for fluoro, chloro, bromo and
iodo compounds, respectively, and the error in DEV is
estimated as G0.05 kcal molK1. The values obtained for
the conformer couplings are presented in Table 5, together
with the calculated values from PCMODEL and from low
temperature NMR experiments.
3.2. Computational features
The joint NMR, theoretical calculations and solvation
theory methodology consists of explaining the behaviour of
the coupling constants and, consequently, the conformer
populations, in terms of the main calculated geometries and
of the solvent. Data from Table 1 show the energies for the
C–O–CaO s-cis isomers, which are by far more stable than
the s-trans isomers, for 1–4 in the vapour phase, according
to DFT calculations. The data for the aa and ee, s-trans,
rotamers (gC, gK and anti; Figs. 1 and 2) were not
included in Table 1, since their energies relative to the
corresponding most stable s-cis rotamer vary from 8.14 to
24.84 kcal molK1, indicating that they are not stable
rotamers. For the s-cis isomers (dihedral angle C–O–
CaO), the main ax–ax conformations (gC and gK) present
slightly higher dipole moments than the main eq–eq
conformation (gK). However, the behaviour of the JH H
1
2
couplings, i.e. their increase with the increase of the solvent
dielectric constant, suggesting a corresponding increase in
the eq–eq conformer population, is in opposition to what
would be expected, if we take into account just the solute
dipole moment. The eq–eq conformers in the C–O–CaO s-
cis isomers have quadrupolar moments (see h in Table 2)
expressively larger than the ax–ax conformers, leading to the
observed behaviour in the couplings, and consequently in the
conformer populations.
4. Discussion
The intrinsic couplings 3J1a,2a calculated through BESTFIT
[12] are in close agreement with those obtained
Table 5
3
Intrinsic JH H couplings (Hz) for 1–4, calculated through BESTFIT and
1
2
PCMODEL, and the experimental values obtained at 183 K, in 1:1 CS2/-
acetone-d6
Compound
BESTFIT
PCMODEL
Experimen-
tal (eq–eq)
3.3. Conformational analysis
ax–ax
eq–eq
ax–ax
eq–eq
Due to the consistent solvent dependence of 3JH H ; these
1
2
3
4
3.77
3.24
2.78
2.46
8.68
9.66
3.83
3.18
3.04
2.62
7.87
8.94
9.26
9.85
8.8
9.8
1
2
couplings were combined with the solvation calculations to
provide a detailed account of the conformational equilibria
of 1–4 via Eq. (1).
9.90
10.1
10.5
10.42

216
M.P. Freitas et al. / Journal of Molecular Structure 734 (2005) 211–217
experimentally at low temperature, suggesting that the
methodology used here is a precise tool for the confor-
mational analysis of trans-2-halo-acetoxycyclohexanes.
The results are also in concordance with previous data on
fluoro, chloro and bromo derivatives [5,22]. Zefirov et al.
can be rationalised in terms of the bond order between the
oxygen (bonded to C-1) and halogen, which can be obtained
from the electron density matrix of the DFT calculations.
The difference between these values for the most stable
eq–eq (where an O/X interaction should be occurring)
and ax–ax (where an O/X interaction cannot occur)
conformers of the fluoro, chloro and bromo compounds
(ree–raa), obtained through the B3LYP/6-311CCg(d,p)
calculations, were 0.023, 0.005 and K0.025, respectively.
Positive values indicate attractive interaction between the
gauche heteroatoms and negative values a repulsive
interaction. These numbers suggest an attractive gauche
effect for the fluoro compound, an interaction neither
attractive nor repulsive for the chloro compound (actually,
slightly attractive) and a repulsive interaction for the bromo
compound. The calculations for the iodo compound were
performed at a less refined level and gave a very poor
conformer energy difference (Table 1). Other recent
interpretations of the gauche effect may be found in the
literature [24–30], where hyperconjugative interaction
(cyclohexyl esters) [31], or an antidestabilisation due to a
poorer overlap between the C–C s-bond forming orbitals
caused by bond bending at the carbon nuclei, are invoked.
1
[22] found from their H-NMR studies, a DGaa–ee value of
1.3 kcal molK1, in CCl4, for the fluoro compound, increas-
ing to 2.0 kcal molK1 in CDCl3 and to 2.4 kcal molK1 in
CD3CN. Buchanan et al. [5] utilising low temperature 13C–
NMR for determination of the conformational
equilibrium in chloro and bromo derivatives in CD2Cl2,
obtained DGaa–ee of 1.0 and 1.2 kcal molK1, respectively.
A great prevalence of the eq–eq conformation in any
solvent was observed for all compounds, the rotamer with
the dihedral angle C–O–CaO s-cis being the preferred one,
due to steric considerations. An electrostatic attraction
between the carbonyl oxygen and the hydrogen in position 1
can also be invoked to explain the greater s-cis stability. It is
known that trans-2-halocyclohexanols present the eq–eq
form almost exclusively, in both the vapour phase and in
solution, due especially to intra/intermolecular hydrogen
bonding [2–5]. The methoxy derivatives of these halohy-
drins have a smaller eq–eq preference, since hydrogen
bonding cannot occur in these systems and, then, only the
classical steric and electrostatic interactions, as well as the
gauche effect, govern their conformational equilibration
[1,7]. The trans-2-halo-acetoxycyclohexanes present an
intermediate behaviour, between the trans-2-halocyclohex-
anols and their methyl ethers. This is due to the large size of
the acetoxy group, which causes a stronger syn-1,3-diaxial
repulsion in the ax–ax form, in comparison to the methoxy
group, favouring more its eq–eq conformation, in relation to
the methoxy derivatives. Moreover, the eq–eq conformation
in the acetoxy compounds is not so stabilised, as it is for the
halohydrins, due to the high energy of the hydrogen bonding
in the latter compounds.
5. Conclusions
The results described here demonstrate the applicability
of the NMR, theoretical and solvation methodology for
the conformational analysis of trans-2-halo-acetoxycyclo-
hexanes, which presented an eq–eq preference in all
solvents and also in the vapour phase. The larger size of
the acetoxy group, in relation to the methoxy group, leads
to a higher eq–eq population for the former derivatives,
due to their stronger repulsive syn-1,3-diaxial interactions
in the ax–ax form. In contrast, the eq–eq prevalence of the
acetoxy compounds is smaller than for trans-2-halocyclo-
hexanols, due to the intra/intermolecular hydrogen bond-
ing present in the latter, which favours the eq–eq
conformation. The governing factors on the conformation-
al equilibrium of the title compounds are steric and
dipolar interactions, and also the gauche effect, especially
for the fluoro derivative.
In polar and moderately polar solvents, where dipolar
repulsion between the polar atoms is minimised, the order in
stability between the ax–ax and eq–eq forms for compounds
2–4 changes, in comparison to the energy values in the
vapour phase and CCl4, i.e. in these non-polar media the
ax–ax population is larger according to ClOBrOI, while
the inverse order is observed in the remaining solvents. This
suggests that non-electrostatic effects, like steric inter-
actions plus the gauche effect, favour the eq–eq form
according the order ClOBrOI. For the fluoro compound,
whose stability does not fit with the expected trend, if the
halogen size and/or electronegativity are taken into account,
the eq–eq conformation is more populated than expected,
indicating an extra stabilisation of this conformation due to
an expressive gauche effect.
Acknowledgements
We acknowledge FAPESP for financial support of this
research and for a scholarship (to M.P.F.) and a fellowship
(to C.F.T.), CNPq for a fellowship (to R.R.) and
CENAPAD-SP for the computer facilities (GAUSSIAN98).
Professor C. H. Collins’ assistance in revising this manu-
script is also gratefully acknowledged.
It is clear then that the effects which govern the
conformational behaviour of trans-2-halo-acetoxycyclohex-
anes are steric and dipolar repulsions and the gauche effect.
The latter can be qualitatively estimated from theoretical
calculations. According to Epiotis [23], the gauche effect

M.P. Freitas et al. / Journal of Molecular Structure 734 (2005) 211–217
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